KR20130086144A - Stable multi-dose compositions comprising an antibody and a preservative - Google Patents

Abstract

The present invention relates to stable, multi-dose liquid compositions comprising proteins, but not exclusively stable antibodies, and to the use of such compositions, in particular for subcutaneous delivery of the stable proteins.

Description

STABLE MULTI-DOSE COMPOSITIONS COMPRISING AN ANTIBODY AND A PRESERVATIVE

The present invention relates to stable, multi-dose liquid compositions comprising proteins, in particular but not exclusively stable antibodies, and in the treatment, in particular the use of such compositions for subcutaneous delivery of said stable proteins.

Immunoglobulins, monoclonal antibodies (mAbs) and humanized antibodies have been developed as pharmaceuticals for many years. There was a clear incentive for the development of multi-dose preparations of monoclonal antibodies because of the possibility of repeat dosing, which creates more convenience for the patient. However, multi-dose preparations must contain antimicrobial agents to protect them from microbial contamination during recovery of the multi-dose. Multi-dose preparations containing preservatives offer several advantages over single dose containers. For example, waste of the product is minimized because different doses of the same container may be obtained. In addition, the dosage can be obtained in the same container for a period of time without worrying about microbial growth. In addition, packaging is minimized because multiple doses are provided in one vial.

Therefore, there is a great need for stable, multi-dose liquid pharmaceutical antibody compositions.

However, the effect of preservatives on protein stability is a major concern. Antimicrobial preservatives are known to interact with proteins and cause stability problems such as aggregation. Thus, identifying formulation-compatible preservatives at concentrations that also provide the desired antimicrobial efficacy is a major challenge during drug development. The general consensus that the development of high concentration preparations of mAbs on physical and chemical stability of mAbs, such as the increased formation of insoluble aggregates as well as the availability of low bioactivity, as well as improving the probability of immunogenic response, poses a serious challenge. have.

Aggregation by the polypeptide during storage of the liquid pharmaceutical composition, leading to loss of therapeutic efficacy of the pharmaceutical composition, may have a deleterious effect on the biological activity of the polypeptide. In addition, aggregate formation may cause other problems such as tubing, membranes, or blocks of pumps when the polypeptide-containing pharmaceutical composition is administered using an infusion system.

US 2004/0009168 (Kaisheva et al) describes IgG preparations for multiple administrations comprising a preservative. WO 2008/071394 (F. Hoffmann-La Roche) describes stable pharmaceutical parenteral preparations containing amyloid-beta peptide antibodies. US 2007/0053871 (Li et al) describes stable pharmaceutical preparations comprising proteins or antibodies, preservatives at destabilizing concentrations and osmotic substances at stabilizing concentrations. WO 00/15224 (Eli Lilly and Company) describes stable, soluble preparations comprising proteins, hydrophobic preservatives and nicotinamides. WO 2008/121615 (MedImmune, Inc) describes high concentration liquid preparations of antibodies. WO 2009/070642 (MedImmune, Inc) describes stable lyophilized preparations of bispecific antibodies. US 2004/0197324 (Genentech, Inc) describes a high concentration of antibody and protein preparations with reduced viscosity, which are stable, relatively isotonic, and low haze. US 2008/0112953 (Amgen, Inc) describes a stable formulation comprising an EGFR antibody and glutamic acid buffer. US 6,875,432 to Genentech, Inc. describes concentrated protein preparations with reduced viscosity. US 6,685,940 (Genentech, Inc) describes stable lyophilized proteins suitable for subcutaneous administration. US 2008/0071063 (MedImmune, Inc) describes stable formulations comprising variant Fc regions that improve stability by reducing the tendency to rapidly aggregate.

According to a first aspect of the invention, there is provided a stable, multi-dose liquid composition comprising an antibody and one or more preservatives.

According to a second aspect of the invention, a stable, multi-dose liquid composition is provided, as defined herein for treatment.

According to a first aspect of the invention, there is provided a stable, multi-dose liquid composition comprising an antibody and one or more preservatives.

Monoclonal antibody preparations containing preservatives, such as phenols, have been reported to generate soluble and insoluble protein aggregates. Although phenols are used in many peptides and protein-based drugs, there are several reports of interactions between these preservatives and protein preparations. In addition, it has been reported that benzyl alcohol causes aggregates of recombinant human interferon-Y (rhIFN-Y), recombinant human granulocyte colony stimulating factor (thGCSF), recombinant human interleukin-1 receptor antagonist (rhIL-1ra), and monoclonal antibody preparations. Has been. It is common sense that most protein aggregation is associated with protein structural degeneration or instability. Benzyl alcohol has been demonstrated to bind with and accelerate the aggregation of partially unfolding proteins. In studies of monoclonal antibody preparations, concentrations of 1% benzyl alcohol resulted in the formation of turbidity and soluble aggregates. Benzyl alcohol at a concentration of at least 2% in the same monoclonal antibody preparation resulted in precipitation of the protein.

The data is provided herein that the preparations containing the antibody in combination with several other preservatives resulted in preparations with low contents of aggregates during 4 weeks of storage at 40 ° C. and 3 months at 5 ° C. and 40 ° C. .

The term "stable composition" denotes a composition having satisfactory physical stability, satisfactory chemical stability or satisfactory physical and chemical stability.

As used herein, the term "physical stability" of a protein composition refers to the biologically inert and / or the protein as a result of unstable interface and interaction with the surface and / or hydrophobic surfaces and / or hydrophobic stress of the protein. Or propensity of the protein to form insoluble aggregates. The physical stability of the aqueous protein composition is assessed by means of visual inspection and / or turbidity measurement after exposing the filled composition to a suitable container (eg cartridge or vial). It is inherent in the mabs of highly concentrated preparations to exhibit opalescence by Raleigh scattering. Thus, a composition cannot be classified as physically unstable with regard to protein aggregation when it exhibits visual haze in sunlight. However, when there is precipitation or phase separation that can occur in the sun, the preparation is classified as physically unsafe.

As used herein, the term “chemical stability” of a protein composition is chemical in the protein structure leading to the formation of a chemical degradation product with potentially lower biological efficacy and / or potentially increased immunogenic properties compared to the original protein structure. Covalent bond changes. Various chemical degradation products may be formed depending on the type and nature of the original protein and the environment in which the protein is exposed. The removal of chemical degradation is largely unavoidable and the increase in chemical degradation products is often seen during storage and the use of protein compositions is well known to those skilled in the art. Most proteins have a tendency to deamidation, a process in which the side chain amide groups of glutaminyl or asparaginyl residues are hydrolyzed to form free carboxylic acids. Other degradation pathways involve the formation of polymer modification products when two or more protein molecules are covalently bonded to each other through disulfide interactions leading to amide group transfer and / or covalently bonded dimer, oligo and polymer degradation products. Pharmaceuticals, Ahem. TJ & Manning MC, Plenum Press, New York 1992).

Oxidation (eg of methionine residues) may be referred to as another various chemical degradation. Chemical stability of protein compositions can be assessed by measuring the amount of chemical degradation products at various time points after exposure to other environmental conditions (formation of degradation products can often be accelerated, for example, by increasing temperature). The amount of each degradation product is often determined by the separation of degradation products dependent on molecular size and / or charge using various chromatographic techniques (eg, SEC-HPLC and / or RP-HPLC).

SEC-HPLC is particularly used for quantification of protein aggregates. Samples may be analyzed using, for example, TSK G3000 SWXL columns, isocratic elution and then UV detection at 214 nm. This method is used to determine% high molecular protein (HMWP) consisting of species of dimer or higher separated by size by monomer IgG content and gel resin. The monomer content and% HMWP are determined with respect to the total protein content detected by the method.

For this reason, as outlined above, stable compositions represent compositions with satisfactory physical stability, satisfactory chemical stability or satisfactory physical and chemical stability. Satisfactory stability of the preparation may be measured by an increase in% polymer protein (Δ% HMWP). The satisfactory stability of the formulation may be that the increase in the formulation during the test period is less than 10% and preferably less than 5% (Δ% HMWP) of the protein found as aggregates. In general, the composition should be stable during use and storage until the shelf life is reached (depending on the recommended use and storage conditions).

As used herein, the terms “protein”, “polypeptide” and “peptide” refer to a compound consisting of at least five constituent amino acids bound by peptide bonds. The constituent amino acids may be amino acid groups encoded by the genetic code and they may be natural amino acids not encoded by the genetic code, as well as synthetic amino acids. Natural amino acids not encoded by the genetic code are, for example, hydroxyproline, y-carboxyglutamate, ornithine, phosphoserine, D-alanine and D-glutamine. Synthetic amino acids are amino acids prepared by chemical synthesis, namely D-alanine and D-leucine, Aib (a-aminoisobutyric acid), Abu (α-aminobutyric acid), Tle (tert-butylglycine), β-alanine, 3 -D-isomers of amino acids encoded by the genetic code, such as aminomethyl benzoic acid and anthranilic acid.

The term "preservative" refers to a pharmaceutically acceptable additive that prevents the growth of microorganisms in the composition. More particularly, the present invention provides multi-dose liquid compositions containing a preservative to protect the composition against microbial contamination.

In one embodiment, the preservative is present in the composition in an amount between 0.001 and 2% (weight / volume). In one embodiment, the preservative is present in the composition in an amount of 0.002 to 1% (weight / volume).

In one embodiment, the one or more preservatives are phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben, benzalkonium chloride, thiomersal or these Is selected from the combination of. In one embodiment, the one or more preservatives are selected from phenol, m-cresol, benzyl alcohol and chlorobutanol.

In one embodiment, the composition comprises a single preservative. In one embodiment, the composition is a single preservative selected from phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben, benzalkonium chloride and thiomersal It includes.

When the composition comprises phenol as a single preservative, the phenol is typically 0.15 or 0.5% (weight / volume), in particular 0.1-0.5% (weight / volume), such as 0.25-0.5% (weight / volume). , In an amount of 0.1 to 1% (weight / volume).

When the composition comprises m-cresol as a single preservative, m-cresol is typically 0.1 to 0.5% (weight / volume), such as 0.15 or 0.35% (weight / volume), especially about 0.3% (weight / volume) Present in the composition in an amount of 0.1 to 1% (weight / volume), such as).

When the composition comprises benzyl alcohol as a single preservative, benzyl alcohol is typically from 0.1 to 1.5% (weight / volume), such as 0.5 or 1.1% (weight / volume), especially about 1% (weight / volume). Like, present in the composition in an amount of 0.1 to 2% (weight / volume).

When the composition comprises chlorobutanol as a single preservative, chlorobutanol is typically 0.25 to 0.75% (weight / volume), such as 0.3 or 0.6% (weight / volume), especially about 0.3 to 0.5% (weight / volume). Present in the composition in an amount of 0.1 to 1% (weight / volume), such as).

When the composition comprises methyl parabens as a single preservative, methyl parabens are typically present in the composition in an amount of 0.1 to 0.5% (weight / volume), such as about 0.2% (weight / volume).

When the composition comprises propyl parabens as a single preservative, propyl parabens are typically present in the composition in an amount of 0.1 to 0.5% (weight / volume), such as about 0.2% (weight / volume).

When the composition comprises phenoxyethanol as a single preservative, phenoxyethanol is typically present in the composition in an amount of 0.1 to 2% (weight / volume), such as about 1% (weight / volume).

When the composition comprises thiomersal as a single preservative, thiomersal is typically present in the composition in an amount of 0.002 to 0.01% (weight / volume).

In a further embodiment, the composition comprises a single preservative selected from phenol, m-cresol, benzyl alcohol and chlorobutanol.

In one embodiment, the composition comprises two or more preservatives. In one embodiment, the composition comprises two preservatives. Surprisingly, data is shown here demonstrating that less amount of aggregate was observed for a composition comprising two preservatives compared to the aggregation observed for the individual preservatives. In a further embodiment, the composition comprises two selected from phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben, benzalkonium chloride and thiomersal Preservatives. In a further embodiment, the composition comprises two preservatives selected from phenol, m-cresol, benzyl alcohol and chlorobutanol. Examples of such compositions comprising two preservatives include phenol and m-cresol; And benzyl alcohol and chlorobutanol.

When two or more preservatives are present in the composition, it will be understood that the concentration of each preservative is typically lower than when a single preservative is used.

For example, when the composition comprises phenol and m-cresol as a composition containing two preservatives, the phenol is typically 0.1 to 0.5% (weight / volume), for example 0.15 or 0.5% (weight / volume) ), And m-cresol is typically present in the composition in an amount of 0.1 to 0.75% (weight / volume) and m-cresol typically is 0.15 to 0.4% (weight / volume), for example 0.18 or 0.35% (weight / volume) Likewise, present in the composition in an amount of 0.1 to 0.5% (weight / volume).

In addition, when the composition comprises benzyl alcohol and chlorobutanol as a composition containing two preservatives, benzyl alcohol is typically 0.4 to 0.9% (weight / volume), for example 0.5 or 0.8% (weight / volume). As such, present in the composition in an amount of 0.25 to 1% (weight / volume) and the m-cresol is typically 0.1 to 0.4% (weight / volume), for example 0.11 or 0.3% (weight / volume) , In an amount from 0.1 to 0.5% (weight / volume).

In one embodiment, the composition further comprises a salt. In some embodiments, the salt may have a buffering capacity at an appropriate pH. In one embodiment, the salt is an inorganic salt, or an organic salt, or a combination of one or more thereof. In one embodiment, the salt is sodium chloride, magnesium chloride, sodium thiocyanate, ammonium thiocyanate, ammonium sulfate, ammonium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiocyanate, ammonium thiocyanate, ammonium sulfate , Ammonium chloride, calcium chloride, arginine hydrochloride, zinc chloride, sodium acetate, amino acids or combinations thereof.

In one embodiment, the salt is sodium chloride or magnesium chloride, optionally combined with other salts. In one embodiment, the salt is arginine hydrochloride. In one embodiment the salt is a combination of an inorganic salt and arginine hydrochloride.

In one embodiment, the salt is an amino acid. In one embodiment, L-stereoisomers of amino acids are used. In one embodiment, the salt is selected from arginine, glycine, lysine, aspartic acid, or glutamic acid, or a combination thereof. In one embodiment, the amino acid is arginine or glycine. In one embodiment, the amino acid is arginine, such as L-arginine. Amino acids may be included in the composition in the form of its salt or in its free form, any suitable.

In one embodiment, the composition further comprises a buffer. In one embodiment, the buffer is a suitable pharmaceutically acceptable buffer, which includes both pharmaceutically acceptable bases and pharmaceutically acceptable acids. In one embodiment, the buffer has a pKa of 4-8, such as 5-7. In some embodiments, the buffer may be a salt.

Examples of pharmaceutically acceptable acids and bases may include inorganic as well as organic non-toxic acids / bases, as is well known in the art. Examples are disodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, maleate, succinate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris (hydroxymethyl)- Amino methane, or mixtures thereof. Each of these specific buffers is an alternative embodiment of the invention. In one embodiment, the pharmaceutically acceptable buffer comprises histidine, maleate, succinate, phosphate, or tris (hydroxymethyl) -amino methane. In one embodiment, the pharmaceutically acceptable buffer comprises histidine.

In one embodiment, the buffer has a pKa value ± 1 pH unit from the target pH of the composition.

In one embodiment, the composition has a pH of 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0 As such, it is buffered at a pH of 5 to 7, or a pH as defined in the range in between. In one embodiment, the composition is at a pH as defined by a pH of 6.0 to 7.0, or a range therebetween, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0. Buffered. In one embodiment, the composition is buffered to a pH of 6.0 to 6.5. In one embodiment, the composition is buffered to a pH of 6.0 or 6.5, such as 6.5.

In one embodiment, the composition further comprises a surfactant. In one embodiment of the invention, the surfactant is a detergent, ethoxylated castor oil, polyglycolated glycerides, ethylated monoglycerides, sorbitan fatty acid esters, polyoxypropylene-polyoxyethylene block polymers (e.g. , Polyethylene derivatives such as Pluronic® F68, polyoxamers 188 and 407, polyoxamers such as Triton X-100), polyoxyethylene sorbitan fatty acid esters, polyoxyethylene and alkylated and alkoxylated derivatives (polysorbates, eg For example, Tween-20, Tween-40, Tween-80 and Brij-35), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, alcohols, glycerol, lectins and phospholipids (eg , Phosphatidyl serine, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, diphosphatidyl glycerol and sphingomyelin), phospholipids (eg , Dipalmitoyl phosphatidic acid) and derivatives of lysophospholipids (eg palmitoyl lysophosphatidyl-L-serine and 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine) And alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholine, for example lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and variants of the polar head group, choline, Lauroyl and myristoyl derivatives of ethanolamine, phosphatidic acid, serine, threonine, glycerol, inositol, and positively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidyl threonine, and glycerophospholipids ( For example, cephalin), glyceroglycolipides (eg, galactopyridoids), sphingoglycolipids (eg, ceramides, gangliosides), dodecylfo Focoline, egg lysolecithin, fusidic acid derivatives (e.g., tauro-dihydrofucidinate, etc.), long chain fatty acids and their salts C6-C12 (e.g., oleic acid and caprylic acid), acylcarnitine And N ^α -acylated derivatives of lysine, arginine or histidine, or long chain acylated derivatives of lysine or arginine, or N ^α -acylated derivatives of dipeptides comprising a combination of lysine, arginine or histidine and neutral or acidic amino acids. , N ^α -acylated derivatives of tripeptides, including neutral amino acids and a combination of two charged amino acids, DSS (docusate sodium, CAS Registry No. [577-11-7]), docuate calcium, CAS registry number [128-49-4]), potassium docusate, CAS registry number [7491-09-0]), SDS (sodium dodecyl sulfate or sodium lauryl sulfate), sodium caprylate, choline acid or these Derivatives, bile acids and their Salts and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-ammonio-1-propane Sulfonates, anionic (alkyl-aryl-sulfonates) monovalent surfactants, zwitterionic surfactants (e.g., N-alkyl-N, N-dimethylammonio-1-propanesulfonates, 3-colamido- 1-propyldimethylammonio-1-propanesulfonate), cationic surfactants (quaternary ammonium base) (eg cetyl-trimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants (eg For example, dodecyl β-D-glucopyranoside), a poloxamine (eg Tetronic), a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine Or a surfactant is an imidazoline derivative, or It may also be selected from the group of mixtures thereof. Each one of these specific surfactants is an alternative embodiment of the present invention. In one embodiment, the surfactant is Tween 80 (ie, polysorbate 80).

The use of surfactants in pharmaceutical compositions is well known to those skilled in the art. For convenience, references are made in Remington: The Science and Practice of Pharmacy, 20th edition, 2000.

In one embodiment, the surfactant is present in the composition in an amount of up to 0.01%. In one embodiment, the surfactant is present in the composition in an amount of 0.001% to 0.005%, such as 0.0075% or less, ie 0.001%. In one embodiment, no surfactant is present.

In one embodiment, the composition further comprises a tonicity modifying agent. Examples of suitable isotonic agents include salts (eg sodium chloride), polyhydric alcohols (eg propylene glycol, glycerol, xylitol, mannitol or D-sorbitol), monosaccharides (glucose or maltose), disaccharides ( For example, sucrose, amino acids (L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine), polyethylene glycol (e.g. PEG 400) or mixtures thereof . In one embodiment, the tonicity agent is sucrose, mannitol, or propylene glycol. In one embodiment, the tonicity agent is sucrose. In some embodiments, the buffers and / or salts (as described above) of the composition will also act as tonicity agents or the tonicity agents will act as buffers and / or salts (and therefore in this case the concentration of the tonicity agent is thus Will be calculated).

In one embodiment, the tonicity agent is between 100 and 200 mM, such as in any one or range between 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200, Present in the composition in an amount of 50 to 250 mM. In one embodiment, the tonicity agent is present in the composition in an amount of 150 mM.

In one embodiment, the composition is isotonic.

According to a further aspect of the invention there is provided a stable, multi-dose liquid composition comprising a protein and one or more preservatives.

In one embodiment, the protein is an immunoglobulin. In one embodiment, the protein is an antibody. In one embodiment, the protein is a monoclonal antibody (mAb). In one embodiment, the protein is an IgG4 antibody.

The term “antibody” refers to monoclonal antibodies (including full length antibodies with immunoglobulin Fc regions), antibody compositions with polyepitope specificity, bispecific antibodies, diabodies, and single-chain molecules, as well as antibodies Fragments (eg, Fab, F (ab ') ₂ , and Fv).

As used herein, the term “monoclonal antibody” refers substantially to an antibody obtained from a population of homologous antibodies, ie, the population comprising individual antibodies is identical except for naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are very specific and are directed against a single antigenic site. In addition to their specificity, monoclonal antibodies have the advantage of being synthesized by hybridoma culture and not contaminated by other immunoglobulins. The modifier “monoclonal” is obtained from substantially the same population of antibodies and will not be understood to characterize the antibody and require production of the antibody by any particular method.

Examples of suitable antibodies that may be formulated in the stable compositions of the invention include 3F8, Abagovomab, Abxiximab, ACZ885 (canakinumab), Adalimumab, Adecamumab Adecatumumab, Afelimomab, Afutuzumab, Alacizumab pegol, Alemtuzumab, Altumomab pentetate, Anatumamob mafetotox (Anatumomab mafenatox), Anrukinzumab (IMA-638), Apolizumab, Arcitumomab, Alizlizumab, Atlizumab (Atlizumab (tocilizumab) ))), Atorolimumab, Bapineuzumab, Basiliximab, Basiliximab, Bavituximab, Bectumomab, Belimumab, Bertilim Mumbimat (Bertilimumab), Besilesomab, Bevacizumab, Bisiromab omab, Vivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Briakinumab, Canakinumab, Canakinumab mercans Canthuzumab mertansine, Capromab pendetide, Catummaxomab, Cetulizomab, Cedelizumab, Certolizumab pegol, Cetuximab, Cetuximab, Citatuzumab boga Citatuzumab bogatox, Citutumumab, Clenoliximab, Cliatuzumab tetraxetan, CNTO 148 (golimumab), CNTO 1275 (Ustekinumab) ustekinumab)), conatumumab, dacetuzumab, dacetuzumab, daclizumab, denosumab, detumomab, dolimomab aritox, dolixi Julixa (Dorlixizumab), ecromeximab, Eculizumab, to Edobacomab, Edrecolomab, Efalizumab, Efungumab, Elsilimomab, Enlimomab pegol, Epitumabab Epitumomab cituxetan, Epratuzumab, Erlizumab, Ertumaxomab, Ertaramaxomab, Etaracizumab, Exbivirumab, Panolesomab, Faraliomab, Faralimab , Felvizumab, Fezakinumab, Figitumumab, Figtoumumab, Fontolizumab, Foravirumab, Presolimumab, Garlicimab, Gantenerumab, Gavilimomab, Gemtuzumab ozogamicin, Golimumab, Gomiliximab, Ibalizumab, Ibrizumab thiuk Cetane (Ibritumomab tiuxetan), Igovomab, Imciromab, Inflix Infliximab, Intetumumab, Inolimomab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab, Iratumumab, Keliximab , Lavetuzumab, Lebrikizumab, Lemalesomab, Lerdelimumab, Lexatumumab, Lixatumumab, Libivirumab, Lintuzumab, Luka Tutumabma, Lumiliximab, Mapatumumab, Maslimomab, Matuzumab, Mepolizumab, Metelimumab, Milatuumab Jumatab (Milatuzumab), Minretumomab, Mitumomab, Morolimumab, Morolimumab, Motavizumab, Muromonab-CD3 (Muromonab-CD3), MYO-029 (Stamolumab (stamulumab)), Nacolomab tafenatox, Naptumomab estafenatox, na Natrilizumab, Nebacumab, Necitumumab, Necitumumab, Nerelimomab, Nimotuzumab, Nofetumomab merpentan, Ocrelizumab ), Odulimomab, Ofatumumab, Omalizumab, Oportuzumab monatox, Oregovomab, Otellixizumab, Pagibacimab Pagibaximab, Palivizumab, Panitumumab, Panobakumab, Pascolizumab, Pemtumomab, Pertuzumab, Pertuzumab (Pexelizumab), Pintumomab, Priliximab, Pritumumab, PRO 140, Rafivirumab, Ramucirumab, Ramibrumumab, Ranibizumab, Laxibizumab Racumibacumab, Regavirumab, Reslizumab, Rilotumumab , Rituximab, Rovatumab, Robatumumab, Rontalizumab, Rovelizumab, Ruplizumab, Satumomab, Sevirumab, Sevirumab Rotuzumab, Sifalimumab, Siltuximab, Siltuximab, Siplizumab, Solanezumab, Sonepizumab, Sontuzumab, Sontuzumab, Stamula Lumulab (Stamulumab), sulesomab (Sulesomab), tacatuzumab tetraxetan, Tadocizumab, Talizizumab, Tanezumab, Tanezumab, Taplitumomab poptox (Taplitumoma) paptox, Tefibazumab, Telimob aritox, Tenatumomab, Tenelliximab, Teplizumab, TGN1412, Ticilimumab (Ticilimumab) Memelimumab (tremelimumab))), tigatuzumab, TNX-355 (ibalizumab), TNX-650, TNX-901 ( Talizumab), tocilizumab (atlizumab), toralizumab, tositumomab, trastuzumab, tremelimumab, tremelimumab Tujuzumab celmoleukin, Tuvirumab, Urtoxazumab, Ustekinumab, Vefaliximab, Vealiximab, Vedolizumab, Veltuzumab (Veltuzumab), Vepalimumab (Vepalimomab), Visilizumab (Visilizumab), Volociximab, Votumumab, Zalutumumab, Zalutumumab, Zanolimumab, Zallimumab Ziralimumab), Zolimomab aritox, and the like.

In one embodiment, the antibody is selected from anti-IL-20, anti-TFPI, anti-IL-21, anti-C5Ar, anti-NKGDA or anti-NKG2a antibodies.

In one embodiment, the antibody is a monoclonal anti-IL-20 antibody. In one embodiment, the antibody is an anti-IL-20 antibody as described in WO 2010/000721. In one embodiment, the anti-IL-20 monoclonal antibody is 15D2 or 5B7 as described in WO 2010/000721.

In one embodiment, the antibody is a monoclonal anti-TFPI antibody. In one embodiment, the antibody is an anti-TFPI antibody as described in PCT / EP2009 / 067598. In one embodiment, the anti-TFPI monoclonal antibody is HzTFPI4F36 as described in PCT / EP2009 / 067598.

It will be appreciated that the present invention finds particular utility when proteins are present in the composition at high concentrations. Thus, in one embodiment, the protein is at a concentration of at least 50 mg / ml, such as at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300 mg / ml exist. In one embodiment, the protein is between 50 mg / ml and 300 mg / ml, for example between 50 mg / ml and 250 mg / ml, for example between 100 mg / ml and 200 mg / ml, for example For example, it is present in the composition in an amount of 100 mg / ml to 150 mg / ml. In one embodiment, the protein is 75 mg / ml to 300 mg / ml, for example 75 mg / ml to 250 mg / ml, for example 75 mg / ml to 200 mg / ml, for example 75 present in the composition at a concentration of mg / ml to 150 mg / ml. In one embodiment, the protein is 100 mg / ml to 300 mg / ml, for example 100 mg / ml to 250 mg / ml, for example 100 mg / ml to 200 mg / ml, for example 100 present in the composition at a concentration of mg / ml to 150 mg / ml.

In one embodiment, the protein composition of the present invention buffered at a pH of 5-7

(a) ≧ 50 mg / ml antibody;

(b) an inorganic salt of 30 mM or less, such as sodium chloride or magnesium chloride;

(c) 0-25 mM amino acids, such as arginine or glycine;

(d) buffers up to 50 mM, such as histidine buffer;

(e) 0.001-0.005% of non-ionic surfactant;

(f) 0.001-2% (weight / volume) of one or more preservatives

.

In one embodiment, the protein composition of the present invention buffered at a pH between 6 and 7

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.001% polysorbate 80;

(f) 0.001-2% (weight / volume) of one or more preservatives

.

In one embodiment, the protein composition of the present invention buffered at a pH of 6.5

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.001% polysorbate 80;

(f) 1.5 mg / ml phenol and 1.8 mg / ml m-cresol

.

In one embodiment, the protein composition of the present invention buffered at a pH of 6.5

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 2 to 6 mg / ml m-cresol;

(f) 85-130 mM sucrose

.

In one embodiment, the protein composition of the present invention buffered at a pH of 6.5

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 4 mg / ml m-cresol;

(f) 105 mM propylene glycol

.

The compositions of the present invention surprisingly demonstrated stability to the formation of polymeric protein (HMWP) for 4 weeks at 40 ° C and for 3 months at 5 ° C and 40 ° C.

Pharmaceutical preparations are prepared comprising antibodies and additives (including one or more preservatives).

In one embodiment, the pharmaceutical compositions of the present invention are stable for at least 6 weeks of use and for at least 3 years of storage.

In one embodiment, the pharmaceutical compositions of the present invention are stable for at least 4 weeks of use and for at least 3 years of storage.

In one embodiment, the pharmaceutical compositions of the invention are stable for at least 4 weeks of use and for at least 2 years of storage.

In one embodiment, the pharmaceutical compositions of the present invention are stable for at least two weeks of use and for at least two years of storage.

In one embodiment, the pharmaceutical compositions of the present invention are stable for at least one week of use and at least six years of storage.

According to a second aspect of the present invention there is provided a stable, multi-dose liquid composition for use in treatment as defined herein.

As used herein, the terms “treatment” and “treating” refer to the management and care of a patient for the purpose of preventing a disease, such as a disease or disorder. The term is intended for alleviating symptoms or complications, for delaying the progression of a disease, disorder or condition, for alleviating and reducing symptoms and complications, and / or for treating or eliminating a disease, disorder or condition, as well as for diseases It is intended to include a full spectrum of treatments for a particular disease the patient suffers from, such as administration of an active compound for the prevention of a condition, which may be understood as the care and care of a patient for the purpose of preventing a disease, condition or disorder. And administration of the active compound to prevent the development of symptoms or complications.

The patient being treated is preferably a mammal; Although especially human, it may also include animals such as dogs, cats, cows, sheep and pigs.

For example, stable compositions of anti-IL-20 antibodies of the invention include inflammatory diseases; Especially psoriasis, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease and psoriatic arthritis or others as described in WO 2010/000721 It may also be used for the treatment of autoinflammatory diseases.

Thus, according to a further aspect, the present invention provides a method of treating such an inflammatory disease comprising administering to a patient a therapeutically effective amount of a stable composition of an anti-IL-20 antibody of the invention.

The present invention also provides stable compositions of the anti-IL-20 antibodies of the invention for use in the treatment of such inflammatory diseases.

The present invention also provides the use of stable compositions of the anti-IL-20 antibodies of the invention in the manufacture of a medicament for the treatment of such inflammatory diseases.

The present invention also provides a stable pharmaceutical composition comprising a stable composition of an anti-IL-20 antibody of the invention for use in the treatment of such inflammatory diseases.

Moreover, stable compositions of the anti-TFPI antibodies of the invention, with or without inhibitors, with or without inhibitors, coagulation disorders, such as hemophilia B or else as described in PCT / EP2009 / 067598 Hemorrhagic disease).

Accordingly, according to a further aspect, the present invention provides a method of treating coagulation disorder comprising administering to a patient a therapeutically effective amount of a stable composition of an anti-TFPI antibody of the invention.

The present invention also provides stable compositions of the anti-TFPI antibodies of the invention for use in the treatment of coagulation disorders.

The invention also provides the use of a stable composition of the anti-TFPI antibodies of the invention in the manufacture of a medicament for the treatment of coagulation disorders.

The invention also provides pharmaceutical compositions comprising stable compositions of the anti-TFPI antibodies of the invention for use in the treatment of coagulation disorders.

It will be appreciated that therapeutic and prophylactic (prophylactic) diets represent separate aspects of the present invention.

The pharmaceutical preparations of the invention are generally suitable for parenteral administration. Parenteral administration may be performed subcutaneously, intramuscularly, intraperitoneally or intravenously by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administration can be performed by means of an infusion pump.

The invention is further described with reference to the following non-limiting examples.

Example

Example  1: anti-40 ° C IL 4-week stability analysis for -40

Twelve formulations were prepared (see Table 1 below). The preparation was prepared from a stock solution containing 150 mg / ml anti-IL-20 antibody and 10 mM histidine buffer, pH 6.5. This stock solution was prepared by conventional UF / DF / UF. Stock solutions of the additives were prepared and mixed in the correct proportions. The final formulation was filled into a 3 ml Penfill® cartridge, type 1 glass. The preparations were stored at 40 ° C. for 4 weeks and analyzed chemically, pharmacologically and biophysically. The increase in the formation of protein aggregates (% HMWP) was determined by SEC-HPLC (as described above).

Table 1: Tested  Composition of Formulations

The results of the stability analysis are shown in Table 2 and all tested formulations were 4 weeks at 40 ° C. It demonstrates that it produces a low aggregate content after storage.

Table 2: SEC - HPLC Is an anti- IL Analyze the increase in% HMWP for -20.

In particular, it should be noted that compositions containing two preservatives (phenol and m-cresol) generally result in less aggregate formation than the result of the individual preservatives alone. Most surprisingly, compositions containing 5 mg / ml phenol alone resulted in an increase of 2.5% HMWP and compositions containing 3.5 mg / ml m-cresol alone resulted in an increase of 3.1% HMWP, but the combination of these two preservatives It can be seen that compositions containing the same concentration resulted in less aggregate formation (1.2% HMWP). An increase of 1.1% is shown in the reference without preservatives.

Efficacy was investigated 4 weeks after storage at 40 ° C. and the results are shown in Table 3. This result demonstrates that overall efficacy has been obtained for all preparations.

Table 3: Anti-Post 4 Week Study IL Of Efficacy -20

Example  2: anti- at 5 ° C and 40 ° C IL 3-month stability analysis for -40

This study was conducted in a similar manner to that described in Example 1 except that it was conducted at 5 ° C. and 40 ° C. for 3 months and the formulation contained sucrose as described in Table 4.

Table 4: Tested Preparation  Composition

The results of the stability analysis at 40 ° C. are shown in Table 5 and all tested formulations resulted in a small amount of aggregate after 1 month storage at 40 ° C.

Table 5: Anti-formed during 3 months storage at 40 ° C IL % To -20 HMWP SEC-HPLC analysis of the increase of

The absolute value of% HMWP is provided because the zero value was not available.

In particular, it should be noted that compositions containing 3.5 mg / ml m-cresol result in the smallest increase in HMWP. The increase in HMWP for this preparation after 3 months storage is lower compared to the reference without preservatives

The results of the stability analysis at 5 ° C. are shown in Table 6 and demonstrate that all tested formulations produced less aggregate content after 12 months storage at 5 ° C.

Table 6: Anti-formed during 12 months at 5 ° C IL Δ% of -20 HMWP of SEC - HPLC  analysis

The absolute value of% HMWP is given because the zero value was not available.

In particular, it should be noted that the compositions containing phenol and m-cresol, respectively, did not show an increase in% HMWP over a period of 12 months at 5 ° C.

Efficacy was investigated after 3 months storage at 40 ° C. and the results are shown in Table 7. This result demonstrates that substantial efficacy has been obtained for all preparations.

Table 7: Anti-After 3 Month Study at 40 ° C IL Of Efficacy -20

The firmness of the formulations was assessed with respect to the cycle of freeze-thaw (-80 ° C. to room temperature) and the temperature and mechanical stress (circulating 4 hours daily during 2 weeks storage at 37 ° C.). Data is provided in Table 8, which indicates that the formulation is robust to physical stress.

Table 8: i) Freeze-thaw stress (10 cycles from -80 ° C to room temperature) and ii ) Combined  Circulation and 2 weeks at 37 ° C Temperature  Exposed to stress mAbs Δ% compared to the zero of the preparation of HMWP Increase

The absolute value of% HMWP after exposure to physical stress was used for this formulation because the zero value of% HMWP was not available.

Visual analyzes were performed on all preparations in light cabinets and architect lamps to assess the possibility of particle formation. At zero all samples were found to be transparent to slightly milky, with no visual particles, using two analytical methods. No difference was found after the preparation was exposed to the stress conditions.

Example  3: anti- IL Results of Modified Preservative Efficacy Test for -20

To analyze the efficacy of other preservatives, preservative efficacy screening tests were performed. The efficacy of the preservatives was measured using a modified USP / Ph Eur preservative efficacy test. In a modified test, the preparation was tested for Staphylococcus aureus. After inoculation, samples were stored for 6 and 24 hours at room temperature and the total bacterial count was measured using a colony calculator. Log reduction values were calculated as logs (start count / final count).

Several bacteria and fungi are tested in the unmodified USP / Ph Eur preservative efficacy test. USP and Ph Eur regulation requirements are listed here in Table 9. It should be noted that the Ph Eur requirements are more stringent than those of the USP, and the Ph Eur requirements suggest the minimum level (B criteria) and recommended suggested levels (A criteria) that must be achieved. The preservative efficacy test was modified in this study to reduce the sample's essential requirements and cost per analysis.

Staphylococcus was selected in the modified preservative test because it is the most resistant pathogen for the selected preparation.

Table 9: Preservative efficacy tests USP  And Ph Eur  Prerequisite

Eleven formulations were prepared (see Table 10 below). The formulations were tested in a modified preservative efficacy test as described above and the results are provided in Table 11.

Table 10: Anti- IL -20 Tested  Composition of the preparation

Table 11: Anti- in Modified Preservative Potency Tests IL Log reduction of Staphylococcus aureus of -20 preparations

The results of the modified preservative efficacy test indicated that preparations with 3 mg / ml phenol complied with Ph Eur's Criteria B and preparations with 5-7 mg / ml phenol and 4-6 mg / ml m-cresol 24 hours Later demonstrates complete killing of staphylococci. The tests performed proved that the formulations were suitable as multi-dose formulations.

The stability of the formulations used in the preservative efficacy screening studies with respect to the formation of% HMWP is provided in Table 12 below. As can be observed, the increase in preservative leads to an increase in% HMWP, but several of the preparations have a stable and satisfactory preservative effect.

Table 12:% for 3 months at 40 ° C HMWP Formation (Δ% HMWP )

* With propylene glycol

Example  4: anti- at 5 ° C and 40 ° C THPI 3-month stability analysis for

This study was conducted in a manner similar to that described in Example 2 except that it was carried out with anti-TFPI antibodies instead of anti-IL-20 antibodies. The tested formulations are as described in Table 13.

Table 13: Tested  Composition of the preparation

The results of the stability analysis at 40 ° C. are shown in Table 14 and demonstrate that all tested formulations resulted in much higher aggregates after 3 months storage at 40 ° C.

Table 14: Anti-formed during 3 month study at 40 ° C IL About -20% HMWP Of increase (Δ% HMWP) SEC - HPLA  analysis

In particular, it can be seen that 5 mg / ml phenol caused a four-fold increase in aggregate formation compared to the reference formulation. In contrast, the same concentration of preservative in the anti-IL-20 containing formulation resulted in only a 2.1-fold increase (see Table 5). However, the results obtained with the combination containing phenol and m-cresol were equivalent to those obtained with anti-IL-20 (ie, 1.9 of aggregate formation for anti-TFPI compared to a 1.8-fold increase for anti-IL-20. Fold increase; see Table 5.

The results of the stability analysis at 5 ° C. are shown in Table 15 demonstrating that all tested formulations produced small amounts of aggregates after 3 months storage at 5 ° C.

Table 15: Anti-formed during 12 month study at 5 ° C IL Δ% of -20 HMWP of SEC - HPLC  analysis

The robustness of the formulation was also evaluated with regard to the cycle of freeze-thaw (-80 ° C. to room temperature) and the thermal and mechanical stress (circulation 4 hours daily during 2 weeks storage at 37 ° C.). The data are provided in Table 16 below, which indicate that the formulation is robust to physical stress.

Table 16: i) Freeze-thaw stress (10 cycles from -80 ° C to room temperature) and ii ) Combined  Circulation and 2 weeks at 37 ° C Temperature  Exposed to stress mAbs Δ% compared to the zero of the preparation of HMWP Increase

Visual analyzes were performed on all preparations in light cabinets and architect lamps to assess the possibility of particle formation. At zero, all samples were found to be transparent to slightly milky without visual particles using two analytical methods. No difference was found after the preparation was exposed to the stress conditions.

The following is a non-limiting list of embodiments of the invention.

Embodiment 1: A stable, multi-dose liquid composition comprising an antibody and one or more preservatives.

Embodiment 2 The composition of embodiment 1, wherein the preservative is present in the composition in an amount of 0.001 to 2% (weight / volume)

Embodiment 3 The composition of embodiment 1 or 2, wherein the preservative is present in the composition in an amount of 0.002 to 1% (weight / volume).

Embodiment 4 The compound of any one of embodiments 1 to 3, wherein the one or more preservatives are phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, Composition selected from propyl parabens, benzalkonium chloride, thiomersal or combinations thereof.

Embodiment 5: The composition of any one of embodiments 1 to 4, wherein the one or more preservatives are selected from phenol, m-cresol, benzyl alcohol and chlorobutanol.

Embodiment 6: The composition of any one of embodiments 1 to 5, wherein the composition comprises a single preservative.

Embodiment 7: The composition of any one of embodiments 1 to 6, wherein the composition is phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben A composition comprising a single preservative selected from benzalkonium chloride and thiomersal.

Embodiment 8: The composition of any of Embodiments 1-7, comprising phenol present in the composition in an amount of 0.1 to 1% (weight / volume) in a single preservative.

Embodiment 9: The composition of any one of Embodiments 1-7, comprising phenol present in the composition in an amount of 0.1 to 0.5% (weight / volume) in a single preservative.

Embodiment 10 The composition of any one of embodiments 1-7, comprising phenol present in the composition in an amount of 0.15 to 0.5% (weight / volume) as a single preservative.

Embodiment 11 The composition of any one of Embodiments 1-7, comprising phenol present in the composition in an amount of 0.25-0.5% (weight / volume) in a single preservative.

Embodiment 12 The composition of any one of embodiments 1-7, comprising m-cresol present in the composition in an amount of 0.1 to 1% (weight / volume) in a single preservative.

Embodiment 13: The composition of any one of embodiments 1-7, comprising m-cresol present in the composition in an amount of 0.1 to 0.5% (weight / volume) in a single preservative.

Embodiment 14 The composition of any one of embodiments 1-7, comprising m-cresol present in the composition in an amount of 0.15 to 0.35% (weight / volume) as a single preservative.

Embodiment 15 The composition of any one of embodiments 1-7, comprising m-cresol present in the composition in an amount of about 0.3% (weight / volume) as a single preservative.

Embodiment 16: The composition of any one of Embodiments 1-7, comprising benzyl alcohol present in the composition in an amount of 0.1 to 2% (weight / volume) in a single preservative.

Embodiment 17 The composition according to any one of embodiments 1 to 7, comprising benzyl alcohol present in the composition in an amount of 0.1 to 1.5% (weight / volume) in a single preservative.

Embodiment 18 The composition of any one of embodiments 1-7, comprising benzyl alcohol present in the composition in an amount of 0.5 to 1.1% (weight / volume) as a single preservative.

Embodiment 19 The composition of any one of embodiments 1-7, comprising benzyl alcohol present in the composition in an amount of about 1% (weight / volume) as a single preservative.

Embodiment 20: The composition of any one of embodiments 1-7, comprising chlorobutanol present in the composition in an amount of 0.1 to 1% (weight / volume) in a single preservative.

Embodiment 21 The composition of any one of embodiments 1-7, comprising chlorobutanol present in the composition in an amount of 0.25 to 0.75% (weight / volume) in a single preservative.

Embodiment 22: The composition of any one of embodiments 1-7, comprising chlorobutanol present in the composition in an amount of 0.3 to 0.6% (weight / volume) as a single preservative.

Embodiment 23: The composition of any one of embodiments 1-7, comprising chlorobutanol present in the composition in an amount of 0.3 to 0.5% (weight / volume) as a single preservative.

Embodiment 24: The composition of any one of embodiments 1-7, comprising methyl parabens present in the composition in an amount of 0.1 to 0.5% (weight / volume) in a single preservative.

Embodiment 25: The composition of any one of embodiments 1-7, comprising methyl paraben present in the composition in an amount of about 0.2% (weight / volume) as a single preservative.

Embodiment 26 The composition of any one of embodiments 1-7, comprising propyl parabens present in the composition in an amount of 0.1 to 0.5% (weight / volume) in a single preservative.

Embodiment 27 The composition of any one of embodiments 1-7, comprising propyl parabens present in the composition in an amount of about 0.2% (weight / volume) in a single preservative.

Embodiment 28 The composition of any one of embodiments 1-7, comprising phenoxyethanol present in the composition in an amount of 0.1 to 2% (weight / volume) as a single preservative.

Embodiment 29: The composition of any one of embodiments 1-7, comprising phenoxyethanol present in the composition in an amount of about 1% (weight / volume) as a single preservative.

Embodiment 30: The composition of any one of embodiments 1-7, comprising thiomersal present in the composition in an amount of 0.002 to 0.01% (weight / volume) as a single preservative.

Embodiment 31 The composition of any one of embodiments 1 to 7, comprising a single preservative selected from phenol, m-cresol, benzyl alcohol and chlorobutanol.

Embodiment 32: The composition of any one of embodiments 1 to 5, comprising two or more preservatives.

Embodiment 33 The composition of embodiment 32, comprising two preservatives.

Embodiment 34: The compound of embodiment 32 or 33, comprising: phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben, benzalkonium chloride and A composition comprising two preservatives selected from thiomersal.

Embodiment 35 The composition of embodiment 34, comprising two preservatives selected from phenol, m-cresol, benzyl alcohol and chlorobutanol.

Embodiment 36 The composition of any one of embodiments 32 to 35, wherein the two preservatives are phenol and m-cresol.

Embodiment 37 The composition of embodiment 36, wherein the phenol is present in the composition in an amount of 0.1 to 0.75% (weight / volume).

Embodiment 38 The composition of embodiment 36 or 37, wherein the phenol is present in the composition in an amount of 0.1 to 0.5% (weight / volume).

Embodiment 39 The composition of any one of embodiments 36 to 38, wherein the phenol is present in the composition in an amount of 0.15 to 0.5% (weight / volume).

Embodiment 40 The composition of any one of embodiments 36 to 39, wherein the m-cresol is present in the composition in an amount of 0.1 to 0.5% (weight / volume).

Embodiment 41 The composition of any one of embodiments 36 to 40, wherein the m-cresol is present in the composition in an amount of 0.15 to 0.4% (weight / volume).

Embodiment 42 The composition of any one of embodiments 36 to 41, wherein the m-cresol is present in the composition in an amount of 0.18 to 0.35% (weight / volume).

Embodiment 43: The composition of any one of embodiments 32 to 35, wherein the two preservatives are benzyl alcohol and chlorobutanol.

Embodiment 44: The composition of embodiment 43, wherein the benzyl alcohol is present in the composition in an amount of 0.25 to 1% (weight / volume).

Embodiment 45: The composition of embodiment 43 or 44, wherein the benzyl alcohol is present in the composition in an amount of 0.4 to 0.9% (weight / volume).

Embodiment 46 The composition of any one of embodiments 43 to 45, wherein the benzyl alcohol is present in the composition in an amount of 0.5 to 0.8% (weight / volume).

Embodiment 47 The composition of any one of embodiments 43 to 46, wherein the chlorobutanol is present in the composition in an amount of 0.1 to 0.5% (weight / volume).

Embodiment 48 The composition of any one of embodiments 43 to 47, wherein the chlorobutanol is present in the composition in an amount of 0.1 to 0.4% (weight / volume).

Embodiment 49: The composition of any one of embodiments 43-48, wherein chlorobutanol is present in the composition in an amount of 0.11 to 0.3% (weight / volume).

Embodiment 50: The composition of any one of embodiments 1 to 49, wherein the buffer is present and has a pKa of 4 to 8.

Embodiment 51: The composition of embodiment 50, wherein the buffer has a pKa of 5 to 7.

Embodiment 52: The method of embodiment 50 or 51, wherein the buffer is present and the buffer is sodium docetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, maleate, succinate, phosphoric acid Sodium dihydrogen, disodium hydrogen phosphate, sodium phosphate, or tris (hydroxymethyl) -amino methane, or mixtures thereof.

Embodiment 53 The composition of embodiment 52, wherein the buffer is histidine, maleate, succinate, phosphate, or tris (hydroxymethyl) -amino methane.

Embodiment 54: The composition of embodiment 53, wherein the buffer is histidine.

Embodiment 55: The composition of embodiment 54, wherein the buffer has a pKa value ± 1 pH unit from the target pH of the composition.

Embodiment 56 The compound of any of embodiments 1-55, wherein the salt is present and the salt is sodium chloride, magnesium chloride, sodium thiocyanate, ammonium thiocyanate, ammonium sulfate, ammonium chloride, calcium chloride, arginine hydrochloride , Zinc chloride and sodium acetate or a combination thereof.

Embodiment 57: The composition of embodiment 56, wherein the salt is sodium chloride or magnesium chloride.

Embodiment 58: The composition of embodiment 57, wherein the salt is sodium chloride.

Embodiment 59 The composition of embodiment 56, wherein the salt is arginine-HCl.

Embodiment 60: The composition of any of embodiments 1-59, wherein the composition has a pH of 5.0 and 7.0.

Embodiment 61: The composition of embodiment 60 having a pH of 6.0 and 7.0.

Embodiment 62: The composition of embodiment 61 having a pH of 6.0 or 6.5.

Embodiment 63 The composition of embodiment 62, having a pH of 6.5.

Embodiment 64: The composition of any one of embodiments 1 to 63, further comprising a surfactant.

Embodiment 65 The composition of embodiment 64, wherein the surfactant is Tween 80 (ie, polysorbate 80).

Embodiment 66: The composition of embodiment 64 or embodiment 65, wherein the surfactant is present in the composition in an amount of less than 0.01%.

Embodiment 67 The composition of any one of embodiments 64 to 66, wherein the surfactant is present in the composition in an amount of less than 0.0075%.

Embodiment 68 The composition of any one of embodiments 64 to 67, wherein the surfactant is present in the composition in an amount of 0.001% to 0.005%.

Embodiment 69 The composition of any one of embodiments 64 to 68, wherein the surfactant is present in the composition in an amount of 0.001%.

Embodiment 70 The composition of any one of embodiments 1 to 63, wherein a surfactant is absent.

Embodiment 71: The composition of any one of embodiments 1 to 70, further comprising an isotonic agent.

Embodiment 72: The composition of embodiment 71, wherein the tonicity agent is sucrose or propylene glycol.

Embodiment 73 The composition of embodiment 72, wherein the tonicity agent is sucrose.

Embodiment 74: The composition of embodiment 72, wherein the tonicity agent is propylene glycol.

Embodiment 75: The composition of any one of embodiments 71 to 74, wherein the tonicity agent is present in an amount of 50 to 250 mM.

Embodiment 76 The composition of any one of embodiments 71 to 75, wherein the tonicity agent is present in an amount of 100 to 200 mM.

Embodiment 77 The composition of any one of embodiments 71 to 76, wherein the tonicity agent is present in an amount of 100 mM.

Embodiment 78: The composition of any one of embodiments 1 to 77, wherein the composition is pharmaceutically acceptable.

Embodiment 79: The stable composition of any of embodiments 1-78, wherein the antibody is present at a concentration of 50 mg / ml to 300 mg / ml.

Embodiment 80: The stable composition of embodiment 79, wherein the antibody is present at a concentration of 75 mg / ml to 300 mg / ml.

Embodiment 81: The stable composition of embodiment 80, wherein the antibody is present at a concentration of 75 mg / ml to 300 mg / ml.

Embodiment 82: The stable composition of embodiment 81, wherein the antibody is present at a concentration of 50 mg / ml to 200 mg / ml.

Embodiment 83: The antibody of embodiment 82, wherein the antibody is present at a concentration of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, or 300 mg / ml. A stable composition, characterized in that.

Embodiment 84: The compound of embodiment 1, wherein

(a) ≧ 50 mg / ml antibody;

(b) an inorganic salt of 30 mM or less, such as sodium chloride or magnesium chloride;

(c) 0-25 mM amino acids, such as arginine or glycine;

(d) buffers up to 50 mM, such as histidine buffer;

(e) 0.001-0.005% of non-ionic surfactant;

(f) 0.001-2% (weight / volume) of one or more preservatives;

(g) 100 mM sucrose

Composition buffered to a pH of 5 to 7, characterized in that it comprises a.

Embodiment 85: The compound of embodiment 1, wherein

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.001% polysorbate 80;

(f) 0.001-2% (weight / volume) of one or more preservatives;

(g) 100 mM sucrose

Composition buffered to a pH of 6 to 7, characterized in that it comprises a.

Embodiment 86: The compound of embodiment 1, wherein

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.001% polysorbate 80;

(f) 1.5 mg / ml phenol and 1.8 mg / ml m-cresol;

(g) 120 mM sucrose

Composition buffered to a pH of 6.5, comprising a.

Embodiment 87: The compound of embodiment 1, wherein

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.01 mg / ml polysorbate 80;

(f) 1.5 mg / ml phenol and 1.8 mg / ml m-cresol;

(g) 120 mM sucrose

Composition buffered to a pH of 5 to 7, characterized in that it comprises a.

Embodiment 88: The compound of embodiment 1, wherein

(a) 100 mg / ml anti-TFPI;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.01 mg / ml polysorbate 80;

(f) 5 mg / ml phenol;

(g) 100 mM sucrose

≪ / RTI >

Embodiment 89: The compound of embodiment 1, wherein

(a) 100 mg / ml antibody;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.01 mg / ml polysorbate 80;

(f) 5 mg / ml phenol;

(g) 95 mM propylene glycol

Composition comprising a.

Embodiment 90: The compound of embodiment 1, wherein

(a) 100 mg / ml anti-IL-20;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 0.01 mg / ml polysorbate 80;

(f) 4 mg / ml m-cresol;

(g) 105 mM propylene glycol

Composition comprising a.

Embodiment 91: The compound of embodiment 1, wherein

(a) 100 mg / ml anti-IL-20;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 2 mg / ml m-cresol;

(f) 129 mM sucrose

≪ / RTI >

Embodiment 92: The compound of embodiment 1, wherein

(a) 100 mg / ml anti-IL-20;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 4 mg / ml m-cresol;

(f) 109 mM sucrose

≪ / RTI >

Embodiment 93: The compound of embodiment 1, wherein

(a) 100 mg / ml anti-IL-20;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 6 mg / ml m-cresol;

(f) 88 mM sucrose

≪ / RTI >

Embodiment 94: The compound of embodiment 1, wherein

(a) 100 mg / ml anti-IL-20;

(b) 25 mM sodium chloride;

(c) 33 mM histidine buffer;

(d) 25 mM arginine;

(e) 4 mg / ml m-cresol;

(f) 105 mM propylene glycol

Composition comprising a.

Embodiment 95: The composition of any one of embodiments 1 to 94, wherein the antibody is an IgG4 subtype.

Embodiment 96: The composition of any one of embodiments 1 to 95, wherein the antibody is a monoclonal antibody.

Embodiment 97: The composition of embodiment 96, wherein the monoclonal antibody is an anti-IL-20 monoclonal antibody.

Embodiment 98 The composition of embodiment 96, wherein the monoclonal antibody is an anti-IL-20 monoclonal antibody as described in WO 2010/000721.

Embodiment 99 The composition of embodiment 96, wherein the monoclonal antibody is an anti-IL-20 antibody 15D2 or 5B7 as described in WO 2010/000721.

Embodiment 100: The composition of embodiment 96, wherein the monoclonal antibody is an anti-TFPI monoclonal antibody.

Embodiment 101 The composition of embodiment 96, wherein the monoclonal antibody is an anti-TFPI monoclonal antibody HzTFPI4F36 as described in PCT / EP2009 / 067598.

Embodiment 102 The stable, multi-dose liquid composition of any of embodiments 1-101, which is used for treatment.

Embodiment 103: A method of treating an inflammatory disease comprising administering to a patient a therapeutically effective amount of the composition of any one of embodiments 97-99.

Embodiment 104 The composition of any one of embodiments 97 to 99, which is used for the treatment of an inflammatory disease.

Embodiment 105: Use of the composition of any one of embodiments 97-99 in the manufacture of a medicament for the treatment of an inflammatory disease.

Embodiment 106 The pharmaceutical composition according to any one of embodiments 97 to 99, comprising an anti-IL-20 composition for use in the treatment of an inflammatory disease.

Embodiment 107: A method of treating coagulation disorder, comprising administering to a patient a therapeutically effective amount of the composition of any one of embodiments 100 or 101.

Embodiment 108 The composition of any one of embodiments 100 or 101, which is used for the treatment of coagulation disorders.

Embodiment 109: Use of the composition of any one of embodiments 100 or 101 in the manufacture of a medicament for the treatment of coagulation disorders.

Embodiment 110: The pharmaceutical composition of any one of embodiments 100 or 101, comprising an anti-IL-20 composition, characterized in that it is used for the treatment of coagulation disorders.

All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference in their entirety and each reference separately, regardless of the inclusion of specific documents made elsewhere, separately provided herein. And to the extent as specifically indicated by reference and to which the full text is set forth (maximum permitted by law).

The use of the terms "a" and "an" and "the" and similar referents in the context of the present invention is intended to encompass both the singular and the plural unless otherwise indicated herein or expressly disclaimed by the context. Will be understood. For example, the phrase "compound" will be understood to represent various "compounds" of the present invention or of the particular described embodiments unless otherwise indicated.

Unless otherwise indicated, all exact values provided herein are representative of that approximation (e.g., all precise exemplary values provided for a particular factor or measurement are also considered to provide such approximation and, where appropriate, Can be transformed into "). If a range is given, the range includes both end values, unless otherwise indicated.

The description of any aspect or aspect of the invention using terms such as “comprising”, “having”, “comprising”, or “comprising” with reference to elements and elements is clearly stated by context or otherwise indicated by context. Unless disclaimed, an attempt is made to provide support for a similar element or aspect of the invention that is "consisting essentially of," "consisting essentially of," or "consisting of" a particular element or elements (eg, , A composition described herein as including a particular element is also to be understood to describe a composition consisting of that element, unless otherwise stated or expressly disclaimed by context).

Claims (15)

A stable, multi-dose liquid composition comprising an antibody and one or more preservatives. The composition of claim 1, wherein the preservative is present in the composition in an amount of 0.001 to 2% (weight / volume), such as 0.002 to 1% (weight / volume). The method of claim 1, wherein the one or more preservatives are phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben, benzalkonium chloride, Thiomersal or combinations thereof, for example phenol, m-cresol, benzyl alcohol and chlorobutanol. The process according to any one of claims 1 to 3, wherein phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben, benzalkonium chloride and A composition comprising a single preservative selected from thiomersal, for example phenol, m-cresol, benzyl alcohol and chlorobutanol. The compound according to any one of claims 1 to 4, wherein phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chlor-m-cresol, methyl paraben, propyl paraben, benzalkonium chloride and Two or more preservatives selected from thiomersal, for example phenol, m-cresol, benzyl alcohol and chlorobutanol, in particular phenol and m-cresol; And benzyl alcohol and chlorobutanol. 6. The composition according to claim 1, wherein the composition is buffered at a pH of 5 to 7, such as a pH of 6.0 to 7.0, such as 6.0 or 6.5, in particular 6.5. 7. The composition of claim 1, further comprising isotonic agents, such as sucrose or propylene glycol. 8. The antibody of claim 1, wherein the antibody is 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, or 300 mg / ml A composition, which is present in the composition at a concentration. 9. A composition according to any one of the preceding claims wherein no surfactant is present. The method of claim 1,
(a) 100 mg / ml antibody;
(b) 25 mM sodium chloride;
(c) 33 mM histidine buffer;
(d) 25 mM arginine;
(e) 0.001% polysorbate 80;
(f) 1.5 mg / ml phenol and 1.8 mg / ml m-cresol;
(g) 120 mM sucrose
Composition buffered to a pH of 6.5, comprising a. The method of claim 1,
(a) 100 mg / ml antibody;
(b) 25 mM sodium chloride;
(c) 33 mM histidine buffer;
(d) 25 mM arginine;
(e) 0.01% polysorbate 80;
(f) 1.5 mg / ml phenol and 1.8 mg / ml m-cresol;
(g) 120 mM sucrose
Composition buffered to a pH of 6.5, comprising a. The method of claim 1,
(a) 100 mg / ml antibody;
(b) 25 mM sodium chloride;
(c) 33 mM histidine buffer;
(d) 25 mM arginine;
(e) 0.01% polysorbate 80;
(f) 1.5 mg / ml phenol and 1.8 mg / ml m-cresol;
(g) 120 mM sucrose
Composition buffered to a pH of 6, comprising a. The stable antibody composition according to any one of claims 1 to 10, which is used for treatment. The stable antibody composition according to any one of claims 1 to 11, which is used for the treatment of an inflammatory disease. The stable composition according to any one of claims 1 to 11, which is used for the treatment of coagulation disorders.